Hydroperylene derivatives

ABSTRACT

Compounds of the formula I  
                 
 
     are suitable for producing pharmaceuticals for the prophylaxis and therapy of diseases in which high blood platelet aggregations occur.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from Provisional U.S.Application No. 60/360,329, filed Feb. 27, 2002, as well as from FederalRepublic of Germany Patent Application No. 10158402.4, filed Nov. 28,2001.

SUMMARY OF THE INVENTION

[0002] The invention relates to hydroperylene derivatives which areformed by the fungus, DSM 14452, during fermentation, or aresubsequently derivatized, to processes for preparing them and to theiruse as pharmaceuticals and inhibitors of blood platelets, as well as tosid novel fungus itself.

BACKGROUND OF THE INVENTION

[0003] Hydroperylene derivatives, such as hexahydroperylene derivativesor octahydroperylene derivatives, are formed by various microorganisms.Examples of known hydroperylene derivatives are:

[0004] Altertoxins I, II and III (M. E. Stark et al. J. Nat. Prod. 49,866-871, 1986),

[0005] Alteichin (D. Robeson et al. Experientia, 40, 1248-1250, 1984),

[0006] the Alterlosins (A. Stierle et al. J. Nat. Prod. 52, 42-47, 1989)and

[0007] Alterperylenol from Alternaria species (T. Okuno et al.Tetrahedron Lett. 24, 5653-5656, 1983);

[0008] Stemphyltoxins and Stemphypyrenol, which are from cultures ofStemphylium botryosum (A. Arnone et al. J. Chem. Soc. Perkin Trans.1,1986, 525-530).

[0009] The altertoxins and the stemphyltoxins are phytotoxins, which, asa result of their mutagenic effect, can also diminish the value of humanfoodstuffs. They have herefore been thoroughly described in more than 70publications (T. J. Schrader et al. Teratog. Carcinog., Mutagen., 21,261-274, 2001). The dangers which emanate from the altertoxins andstemphyltoxins are naturally dealt with in this literature, includingthe wide distribution, and the cancer-causing effect, of thesecompounds, which contain epoxides (oxiranes). In addition to this,alterperylenol has been reported to have a weak telomerase-inhibitingeffect (K-I. Togashi et al. Oncol. Res. 10, 449-453, 1998); however, at30 μM, the IC₅₀ value, which is characteristic for inhibition of theenzyme, is low.

[0010] Thromboembolic diseases are the most frequent cause of death,particularly in the western industrial nations. An effective prophylaxisand therapy for these diseases is therefore of exceptional importance. Athrombus is understood as being a blood clot which has been formedintravitally and intravascularly. Thrombi are formed followingthrombocyte aggregation in arteries, in particular. Damage to the bloodvessel wall, retarded blood flow and accelerated clotting all favorthrombus formation. The thrombocytes (blood platelets) are disc-shaped,anucleate blood cells which ensure hemostasis and blood coagulation wheninjury occurs. Thrombocytes bring about hemostasis by means ofaggregation in a complicated process; thrombocyte aggregation isconsequently an essential process for homeotherms. Hypofunction of thethrombocytes leads to severe hemorrhages, even in the case of relativelysmall injuries; on the other hand, an increased tendency towardscoagulation increases the danger of thrombosis and embolism. Sinceplatelet hyperfunction, in particular, frequently has fatalconsequences, several substances have already been employed asinhibitors of thrombocyte aggregation. Those which are well knowninclude acetylsalicylic acid (Aspirin®), ticlopidine (Tiklyd®) and therelated clopidogrel; however, because of side-effects, the use of allthese preparations is restricted. For this reason, there is a great needfor inhibitors of intracellular platelet activation, which can be usedfor the therapy and long-term prophylaxis of arterial thromboembolicevents. Agents of this nature can be employed, for example, inconnection with myocardial infarction, in connection with unstableangina or in connection with strokes.

DETAILED DESCRIPTION OF THE INVENTION

[0011] In the endeavor to find effective compounds for preventing ortreating blood coagulation diseases, it has now been found thatthioperylenol, which is formed by the fungal strain DSM 14452, and otherhydroperylene derivatives, are able to effectively inhibit bloodplatelet aggregation.

[0012] The invention, therefore, relates to a compound of formula I

[0013] including all stereoisomeric forms of said compound of formula I,mixtures of said forms and compounds in any ratio, and physiologicallytolerated salts thereof, wherein: R1, R2, R3, R4, R5, R6, R7, R8, R10and R11 are independently selected from the group consisting of

[0014] hydrogen;

[0015] (C₁-C₆)-alkyl, in which alkyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of:

[0016] —OH; ═O; —O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of:

[0017] —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is astraight or branched chain; —O—(C₂-C₆)-alkynyl, in which alkynyl is astraight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: : —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; -aryl, in which aryl is unsubstitutedor substituted by one, two or three substituents independently selectedfrom the group consisting of: halogen; —(C₁-C₄)-alkyl, in which alkyl isa straight or branched chain; —O—(C₁-C₆)-alkyl, in which alkyl is astraight or branched chain; —OH and —(C₁-C₄)-alkyl, in which alkyl is astraight or branched chain and is substituted by one, two or threesubstituents selected from the group consisting of halogen; —C(O)—OH;—C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH₂ and halogen;

[0018] (C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chainand is unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of:

[0019] —OH; ═O; —O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain;

[0020] —O—(C₂-C₆)-alkenyl, in which alkenyl is a straight or branchedchain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain;

[0021] —O—(C₂-C₆)-alkynyl, in which alkynyl is a straight or branchedchain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: : —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; -aryl, in which aryl is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —OH and —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain and is substituted one, two or three times by halogen;—C(O)—OH;

[0022] —C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is a straightor branched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH₂ and halogen;

[0023] (C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chainand is unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of:

[0024] —OH; ═O; —O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain;

[0025] —O—(C₂-C₆)-alkenyl, in which alkenyl is a straight or branchedchain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)— alkyl, in which alkyl is a straight orbranched chain; —O—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; -aryl, in which aryl is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: halogen;

[0026] (C₁-C₄)-alkyl, in which alkyl is a straight or branched chain;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain; —OHand —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain andis substituted one, two or three times by halogen; —C(O)—OH;—C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain;

[0027] —NH—(C₂-C₆)-alkenyl, in which alkenyl is a straight or branchedchain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of:

[0028] —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is astraight or branched chain; —NH₂ and halogen;

[0029] —O—R⁹, in which R⁹ is selected from the group consisting of:(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —OH; ═O;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OH;and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;-aryl, in which aryl is unsubstituted or substituted by one, two orthree substituents independently selected from the group consisting of:halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain; —OHand —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain andis substituted one, two or three times by halogen; —C(O)—OH;—C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH; and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH₂ and halogen;

[0030] (C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chainand is unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —OH; ═O;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OH;and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;-aryl, in which aryl is unsubstituted or substituted by one, two orthree substituents independently selected from the group consisting of:halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain; —OHand —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain andis substituted one, two or three times by halogen; —C(O)—OH;—C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH; and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH₂ and halogen;

[0031] (C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chainand is unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —OH; ═O;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OH;and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂, ═N—OHand ═N—O—(C₀-C₆)-alkyl, in which alkyl is a straight or branched chain;-aryl, in which aryl is unsubstituted or substituted by one, two orthree substituents independently selected from the group consisting of:halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain; —OHand —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain andis substituted one, two or three times by halogen; —C(O)—OH;—C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH; and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH₂ and halogen;

[0032] —NH—R⁹, in which R⁹ is as defined above;

[0033] —NH—C(O)—H;

[0034] —NH—C(O)—R⁹, in which R⁹ is as defined above;

[0035] —NH-aryl, in which aryl is unsubstituted or independentlysubstituted one, two or three times by R⁹, in which R⁹ is as definedabove:

[0036] ═N—OH;

[0037] ═N—O—R⁹, in which R⁹ is as defined above;

[0038] —S—H;

[0039] —S—R⁹, in which R⁹ is as defined above;

[0040] —S(O)—R⁹, in which R⁹ is as defined above;

[0041] —S(O)₂—R⁹, in which R⁹ is as defined above; and

[0042] —SO₂, with the following further alternatives to the foregoingdefinition:

[0043] a) either R4 and R5 or R10 and R11, together with the carbonatoms to which they are,respectively, bonded, may form a 3-, 4-, 5- or6-membered heteroalkyl or heteroaryl ring system which contains one ortwo heteroatoms selected from the group consisting of oxygen, nitrogenand sulfur; and

[0044] b) the bond between the ring carbons indicated as —C₁₄-C₁₅— informula I may be either a single bond or a double bond; and the furtherproviso that:

[0045] c) R7 is not hydrogen.

[0046] The invention also relates to a compound of formula I, wherein

[0047] each of R1, R2, R3 and R6 is —OH;

[0048] R4 and R5, together with the carbon atom to which they arebonded, form an epoxide;

[0049] R7 is the radical —S—CH₂—CHOH—COOH;

[0050] R8 is ═O;

[0051] R10 and R11 are each hydrogen;

[0052] and the bond between —C₁₄-C₁₅— is a single bond.

[0053] The invention also relates to optically pure compounds of theformula I and to their stereoisomeric mixtures, such as enantiomericmixtures and diasteromeric mixtures, in any ratio to each other.

[0054] The term “halogen” is understood as meaning fluorine, chlorine,bromine or iodine. The term “(C₁-C₆)-alkyl” is understood as meaninghydrocarbon radicals whose carbon chain is straight-chain or branchedand contains from 1 to 6 carbon atoms, for example methyl, ethyl,propyl, i-propyl, butyl, tertiary butyl, pentyl and hexyl. The term“(C₂-C₆)-alkenyl” is understood as meaning hydrocarbon radicals whosecarbon chain is straight-chain or branched and contains from 2 to 6carbon atoms, and which exhibits one, two or three double bonds, forexample the radicals allyl, crotyl, 1-propenyl, penta-1,3-dienyl,pentenyl and hexenyl. The term “(C₂-C₆)-alkynyl” is understood asmeaning hydrocarbon radicals whose carbon chain is straight-chain orbranched and contains from 2 to 6 carbon atoms and which exhibits one ortwo triple bonds, for example the radicals propynyl, butynyl andpentynyl. The term “aryl” is understood as meaning the radicals phenyl,benzyl, 1-naphthyl and 2-naphthyl. The expression “R4 and R5, togetherwith the carbon atoms to which they are in each case bonded, form a 3-,4-, 5- or 6-membered ring system which is aromatic or saturated andwhich contains one or two heteroatoms from the series oxygen, nitrogenor sulfur” is understood as meaning radicals such as epoxide, aziridine,azetidine, azetine, pyrrole, pyrrolidine, pyridine, piperidine,tetrahydropyridine, pyrazole, imidazole, pyrazoline, imidazoline,pyrazolidine, imidazolidine, pyridazine, pyrimidine, pyrazine,piperazine, pyran, oxazole, isoxazole, 2-isoxazoline, isoxazolidine,morpholine, oxothiolane, thiopyran, thiazole, isothiazole,2-isothiazoline, isothiazolidine or thiomorpholine.

[0055] The invention furthermore relates to the compound of the formulaII

[0056] In the description which follows, the compound of the formula IIis termed thioperylenol (empirical formula: C₂₃H₂₀NO₉S; molecular weight472.47) and to the physiologically tolerated salts thereof.

[0057] The invention furthermore relates to a process for preparing acompound of formula I, and/or a stereoisomeric form of a compound of theformula I and/or mixtures of these forms in any ratio, and/or aphysiologically tolerated salt of a compound of formula I, which processcomprises

[0058] a) culturing the microorganism DSM 14452, or its mutants orvariants, in an aqueous nutrient medium and isolating and purifying thecompound thioperylenol, or

[0059] b) converting thioperylenol, by means of chemical derivatization,into a compound of the formula I, or

[0060] c) resolving a compound of the formula I, which has been preparedby methods a) or b) and which, because of its chemical structure,appears in enantiomeric forms, into the pure enantiomers by formingsalts with enantiomerically pure acids or bases, by chromatography onchiral stationary phases or by derivatizing with chiral,enantiomerically pure compounds such as amino acids, separating thediastereomers which are thus obtained and eliminating the chiralauxiliary groups, or

[0061] d) either isolating the compound of the formula I which has beenprepared by the methods a), b) or c) in free form or, when acidic orbasic groups are present, converting it into physiologically toleratedsalts.

[0062] The microorganism DSM 14452 (internal designation ST003367)belongs to the fungal group and possesses a white substrate mycelium andvery little aerial mycelium and was deposited on Aug. 3, 2001, under theconditions of the Budapest Treaty, in the DSMZ-Deutsche Sammlung vonMikroorganismen und Zellkulturen [German collection of microorganismsand cell cultures] GmbH, Mascheroder Weg 1b, D-38124 Braunschweig, underthe number DSM 14452.

[0063] Variants of DSM 14452 are understood as being DSM 14452 strainswhich have been obtained by isolating individual colonies from a cultureof DSM 14452 on the proviso that they produce thioperylenol. Mutants ofDSM 14452 are understood as being DSM 14452 strains which have beenobtained from a culture of DSM 14452 after mutation, with the provisothat they produce thioperylenol. Mutants of DSM 14452 can be generated,in a manner known per se, by physical means, for example irradiation,such as ultraviolet or X-ray radiation, or by using chemical mutagens,for example ethyl methanesulfonate (EMS);2-hydroxy-4-methoxybenzophenone (MOB) orN-methyl-N′-nitro-N-nitrosoguanidine (MNNG).

[0064] The mutants are found, for example, by taking samples from theculture medium and determining the inhibitory effect of thioperylenol.

[0065] Thioperylenol is produced by culturing DSM 14452. The nutrientsolution contains carbon sources, such as sucrose, corn starch,dextrose, lactose, D-mannitol, molasses or malt extract, and nitrogensources, such as soybean flour, peanut flour, proteins, peptones,peptides, tryptones, meat extract, yeast extract or ammonium salts ornitrates.

[0066] The nutrient solution also contains inorganic salts such assodium hydrogen phosphate, sodium chloride, calcium chloride, calciumsulfate, calcium carbonate, magnesium sulfate or potassium hydrogenphosphate. In addition, it is also possible to add fat, such as methyloleate or soybean oil, to the nutrient medium. Besides that, traceelements, such as iron salts, manganese salts, copper salts, zinc saltsor cobalt salts, or other metal salts, are also added.

[0067] A preferred nutrient solution contains from about 0.05% to about5%, preferably from about 1% to about 3%, potato dextrose and from about0.05% to about 3%, preferably from about 0.05% to about 1%, yeastextract. The percentages relate to the weight of the total nutrientsolution.

[0068] DSM 14452 is cultured at temperatures of from about 18° C. toabout 35° C., preferably at from about 23° C. to about 28° C., and at pHvalues of from about 3 to about 10, preferably from about 5 to about 9,particularly preferably at values of from about 4 to about 6. Theculture is carried out aerobically, initially in shaking flasks and,after that, in a fermenter while stirring and aerating with air or pureoxygen. The microorganisms are cultured in the fermenters for a periodof from about 48 to about 720 hours, preferably of from about 72 toabout 144 hours.

[0069] The formation of thioperylenol reaches its maximum after fromabout 96 to about 144 hours.

[0070] The fungal strain DSM 14452 also forms mixtures of severalcompounds of formula I in the nutrient solution. The quantitativeproportion of the compounds of formula I in the mixture can varydepending on the composition of the nutrient solution. In addition, thecomposition of the medium can be used to direct the synthesis ofindividual compounds of formula I such that the microorganism eitherdoes not produce individual compounds of formula I at all or onlyproduces them in a quantity which is below the limit of detection.

[0071] Thioperylenol is either isolated directly from the nutrientsolution or isolated after the cells have been separated off, forexample by means of centrifugation or filtration. The thioperylenol canbe isolated by extracting with solvents or by adsorbing on resins suchas XAD 16, HP 20, MCI Gel® CHP20P or ion exchangers. It is purified, forexample, by chromatography on adsorption resins such as on Diaion® HP-20(Mitsubishi Casei Corp., Tokyo), on Amberlite® XAD 7 (Rohm and Haas,USA), or on Amberchrom® CG (Toso Haas, Philadelphia, USA). Theseparations can be carried out over a wide pH range. The range of pH 1to pH 9 is preferred, with the range of pH 2 to pH 8 being particularlypreferred. In addition to this, reverse phase supports, which are usedwithin the context of high pressure liquid chromatography (HPLC), arealso suitable. Another isolation method is that of using molecularsieves such as Fractogel® TSK HW-40S or Sephadex® LH-20.

[0072] The microbiologically produced thioperylenol is used as thestarting material for preparing the thioperylenol derivative. Thecompounds of formula I are prepared in a manner known per se; forexample, the epoxide group of the thioperylene can be converted byhydrolysis or solvolysis into alcohols or esters. Epoxides are veryreactive compounds which, in addition to water and acids, also add onother nucleophilic reagents, such as alcohols, thiols, amines andGrignard compounds, in the presence of acidic or basic catalysts. Theaddition of hydrogen cyanide leads further on to(3-hydroxy-propionitrile derivatives. In addition to this, epoxides canbe rearranged to give carbonyl-derivatives, with this rearrangementbeing catalyzed, for example, by Lewis acids. In addition, the reactionproducts can be subjected to further reactions. These reactions areknown per se and are described, for example, by Jerry March, AdvancedOrganic Chemistry, John Wiley & Sons, 4^(th) Edition, 1992.

[0073] Other derivatives are obtained if the 3-thio-lactic acid radicalof the thioperylenol is reacted reductively or oxidatively. It can alsobe advantageous to use the sulfide as what is termed a leaving group andreplace it with other suitable radicals in a manner known from theliterature. In order to carry out reactions selectively, it can beadvantageous to introduce suitable protecting groups, in a manner knownper se, prior to the reaction. The protecting groups are eliminatedafter the reaction and the reaction product is then purified.

[0074] Pharmacologically tolerated salts of compounds of formula I areunderstood as being both inorganic and organic salts, as are describedin Remington's Pharmaceutical Sciences (17th edition, page 1418 (1985)).Physiologically tolerated salts are prepared in a manner known per sefrom compounds of formula I, including their stereoisomeric forms, whichare capable of forming salts. With basic reagents, such as hydroxides,carbonates, hydrogen carbonates, alcoholates and ammonia, or organicbases, for example, trimethylamine, triethylamine, ethanolamine ortriethanolamine, or else basic amino acids, for example, lysine,ornithine or arginine, the carboxylic acid forms stable alkali metalsalts, alkaline earth metal salts or, where appropriate, substitutedammonium salts. If a compound of formula I possesses basic groups, it isalso possible to prepare stable acid addition salts with strong acids.Both inorganic acids and organic acids, such as hydrochloric acid,hydrobromic acid, sulfuric acid, benzenesulfonic acid, phosphoric acid,methanesulfonic acid, p-toluenesulfonic acid, 4-bromobenzenesulfonicacid, trifluoromethylsulfonic acid, cyclohexylamidosulfonic acid, aceticacid, oxalic acid, tartaric acid, succinic acid and trifluoroaceticacid, are suitable for this purpose.

[0075] The invention also relates to pharmaceuticals which arecharacterized by an effective content of at least one compound of theformula I and/or a physiologically tolerated salt of the compound of theformula I and/or an optionally stereoisomeric form of the compound ofthe formula I, together with a pharmaceutically suitable andphysiologically tolerated carrier substance, additive and/or otheractive compounds and auxiliary substances.

[0076] On account of their pharmacological properties, the compounds offormula I are suitable for the prophylaxis and therapy of all thosediseases in which high blood platelet aggregations occur and which arecaused by thrombus formation or embolisms. These diseases include, forexample, myocardial infarction, unstable angina pectoris, stroke,transitory ischemic attacks and peripheral arterial occlusion diseases(peripheral vascular disease) such as intermittent claudication.

[0077] The invention also relates to the use of at least one compound offormula I and/or all stereoisomeric forms of the compounds of formula Iand/or mixtures of these forms in any ratio, and/or a physiologicallytolerated salt of the compound of the formula I, for producingpharmaceuticals for the prophylaxis and therapy of diseases in whichhigh blood platelet aggregations occur, where R1, R2, R3, R4, R5, R6,R7, R8, R10 and R11 R1, R2, R3, R4, R5, R6, R7, R8, R10 and R11 areindependently selected from the group consisting of

[0078] hydrogen;

[0079] (C₁-C₆)-alkyl, in which alkyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of:

[0080] —OH; ═O; —O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of:

[0081] —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is astraight or branched chain; —O—(C₂-C₆)-alkynyl, in which alkynyl is astraight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: : —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; -aryl, in which aryl is unsubstitutedor substituted by one, two or three substituents independently selectedfrom the group consisting of: halogen; —(C₁-C₄)-alkyl, in which alkyl isa straight or branched chain; —O—(C₁-C₆)-alkyl, in which alkyl is astraight or branched chain; —OH and —(C₁-C₄)-alkyl, in which alkyl is astraight or branched chain and is substituted by one, two or threesubstituents selected from the group consisting of halogen; —C(O)—OH;—C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₀-C₆)-alkyl, in which alkyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH₂ and halogen;

[0082] (C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chainand is unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of:

[0083] —OH; ═O; —O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₂-C₆)-alkenyl, in which alkenyl is a straightenbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of:: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; -aryl, in which aryl is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —OH and —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain and is substituted one, two or three times by halogen;—C(O)—OH; —C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is astraight or branched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is astraight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkenyl, in which alkenylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkynyl, in which alkynylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH₂ and halogen;

[0084] (C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chainand is unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of:

[0085] —OH; ═O; —O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)— alkyl, in which alkyl is a straight orbranched chain; —O—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; -aryl, in which aryl is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —OH and —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain and is substituted one, two or three times by halogen;—C(O)—OH; —C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is astraight or branched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is astraight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkenyl, in which alkenylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkynyl, in which alkynylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH₂ and halogen;

[0086] —O—R⁹, in which R⁹ is selected from the group consisting of:(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —OH; ═O;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OH;and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;-aryl, in which aryl is unsubstituted or substituted by one, two orthree substituents independently selected from the group consisting of:halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain; —OHand —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain andis substituted one, two or three times by halogen; —C(O)—OH;—C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH; and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH₂ and halogen;

[0087] (C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chainand is unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —OH; ═O;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OH;and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;-aryl, in which aryl is unsubstituted or substituted by one, two orthree substituents independently selected from the group consisting of:halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain; —OHand —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain andis substituted one, two or three times by halogen; —C(O)—OH;—C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH; and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH₂ and halogen;

[0088] (C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chainand is unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of:—OH; ═O;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OH;and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;-aryl, in which aryl is unsubstituted or substituted by one, two orthree substituents independently selected from the group consisting of:halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain; —OHand —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain andis substituted one, two or three times by halogen; —C(O)—OH;—C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH; and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH₂ and halogen;

[0089] —NH—R⁹, in which R⁹ is as defined above;

[0090] —NH—C(O)—H;

[0091] —NH—C(O)—R⁹, in which R⁹ is as defined above;

[0092] —NH-aryl, in which aryl is unsubstituted or independentlysubstituted one, two or three times by R⁹, in which R⁹ is as definedabove:

[0093] ═N—OH;

[0094] ═N—O—R⁹, in which R⁹ is as defined above;

[0095] —S—H;

[0096] —S—R⁹, in which R⁹ is as defined above;

[0097] —S(O)—R⁹, in which R⁹ is as defined above;

[0098] —S(O)₂—R⁹, in which R⁹ is as defined above; and

[0099] —SO₂, with the following further alternatives to the foregoingdefinition:

[0100] a) either R4 and R5 or R10 and R11, together with the carbonatoms to which they are,respectively, bonded, may form a 3-, 4-, 5- or6-membered heteroalkyl or heteroaryl ring system which contains one ortwo heteroatoms selected from the group consisting of oxygen, nitrogenand sulfur; and

[0101] b) the bond between the ring carbons indicated as —C₁₄-C₁₅— informula I may be either a single bond or a double bond; and the furtherproviso that:

[0102] c) R7 is not hydrogen.

[0103] The invention also relates to a process for producing apharmaceutical, which process comprises bringing at least one compoundof the formula I, together with a pharmaceutically suitable andphysiologically tolerated excipient and, where appropriate, othersuitable active compounds, additives or auxiliary substances, into asuitable form for administration.

[0104] Examples of suitable solid or galenic preparation forms aregranules, powders, sugar-coated tablets, tablets, (micro)capsules,suppositories, syrups, juices, suspensions, emulsions, drops orinjectable solutions and preparations having a protracted release of theactive compound, in the production of which use is made of customaryadjuvants such as carrier substances, disintegrants, binders, coatingagents, swelling agents, glidants or lubricants, flavorings, sweetenersand solubilizers. Frequently employed auxiliary substances which may bementioned are: magnesium carbonate, titanium dioxide, lactose, mannitoland other sugars, talc, milk protein, gelatin, starch, cellulose and itsderivatives, animal and vegetable oils, such as cod liver oil, sunfloweroil, peanut oil or sesame oil, polyethylene glycol and solvents, such assterile water and monohydric or polyhydric alcohols, such as glycerol.

[0105] The pharmaceutical preparations are preferably produced andadministered in dosage units, with each unit containing, as the activeconstituent, a particular dose of the compound of the formula Iaccording to the invention. In the case of solid dosage units, such astablets, capsules, sugar-coated tablets or suppositories, this dose canbe from 0.1 mg/kg of body weight to 1,000 mg/kg of body weight,preferably from 0.2 mg/kg of body weight to 100 mg/kg of body weight.They are expediently administered in dosage units which contain at leastthe effective daily quantity of the compound of the formula I, forexample up to 1000 mg, preferably, however, from about 50 to 300 mg and,in the case of injection solutions in ampule form, up to about 300 mg,preferably, however, from about 10 to 100 mg.

[0106] Daily doses of from about 20 mg to 1,000 mg, preferably fromabout 100 mg to 500 mg, of active compound, depending on the activity ofthe compound according to formula I, are indicated for treating an adultpatient of about 70 kg in weight. However, it may possibly also beappropriate to use higher or lower daily doses. The daily dose can beadministered either by means of a once-only administration in the formof a single dosage unit or of several smaller dosage units or by meansof a repeated administration of subdivided doses at particularintervals.

[0107] The microorganism DSM 14452 is also part of the subject matter ofthe invention.

[0108] The following examples are intended to illustrate the inventionwithout thereby restricting the scope of the invention in any way.

EXAMPLE 1 Preparing a Glycerol Culture of the Fungal Strain DSM 14452

[0109] 30 ml of nutrient solution (malt extract, 2.0%, yeast extract,0.2%, glucose, 1.0%, (NH₄)₂HPO₄, 0.05%, pH 6.0) in a sterile 100 mlErlenmeyer flask were inoculated with the fungal strain ST 003367, DSM14452, and incubated at 25° C. and 140 revolutions per minute (rpm) on arotating shaker for 6 days. 1.5 ml of this culture were subsequentlydiluted with 2.5 ml of 80% glycerol and stored at −135° C.

EXAMPLE 2 Preparing a Preliminary Culture of the Fungus DSM 14452 (in anErlenmeyer Flask)

[0110] 100 ml of nutrient solution (malt extract, 2.0%, yeast extract,0.2%, glucose, 1.0%, (NH₄)₂HPO₄, 0.05%, pH 6) in a sterile 300 mlErlenmeyer flask were inoculated with the fungal strain ST 003367, DSM14452, and incubated at 25° C. and 140 rpm on a rotating shaker for 4days. 2 ml of this preliminary culture were subsequently required forpreparing the main cultures.

EXAMPLE 3 Preparing Thioperylenol by Culturing the Fungal Strain DSM14452

[0111] In the flask:

[0112] A sterile 300 ml Erlenmeyer flask containing 100 ml of thefollowing nutrient solution: potato dextrose, 2.4%, yeast extract, 0.2%,pH 5.1, was inoculated with a culture which had been grown on a slopingtube (same nutrient solution but containing 2% agar), or with 2 ml of apreliminary culture, as described in example 2, and incubated at 25° C.and 140 rpm on a shaker. The maximum production of one or more compoundsof the formula I was achieved after about 96 hours.

[0113] In the fermenter:

[0114] The preliminary culture of the strain ST 003367, DSM 14452, wasgrown at 25° C. and 140 rpm in a 2 L Erlenmeyer flask (volume in theflask, 500 mL). The fermenter was inoculated after 72 h. The strain wasfermented in 8 L fermenters. The conditions for the fermentation wereset as follows and led to the production of the compound according tothe invention thioperylenol:

[0115] Temperature=25° C.; gassing=0.5 wm; rotational speed=200-220revolutions per minute (rpm); inoculum=6%; culturing time=96 hours (h).

[0116] Nutrient Media: Preliminary culture Malt extract 20 g/L Yeastextract 2 g/L Glucose 10 g/L (NH₄)₂PO₄ 0.5 g/l Main culture Potatodextrose broth 24 g/L Yeast extract 2 g/L Desmophene 1.25 mL/L

[0117] It was possible to suppress foam formation by repeatedly addingethanolic polyol solution. The maximum production was reached after fromabout 96 to 144 hours.

EXAMPLE 4 Isolating the Natural Product Thioperylenol

[0118] 15 liters of the culture solution obtained in accordance withexample 3 were freed from the cell mass by centrifugation. The mycelium(1.5 liters) is extracted with 5 liters of methanol. The clear alcoholicphase was concentrated down to about 2 liters under reduced pressure andcombined with the culture filtrate. The turbid aqueous solution was thenloaded onto a 1 L-capacity column which was filled with the absorptionresin MCI Gel® CHP20P. Column dimensions: width x height: 6 cm×35 cm.The column was eluted with a solvent gradient of 0.1% ammonium formatebuffer, pH 4.5, in water after 2-propanol. The column effluent (60mL/minute) was collected in fractions of in each case 220 mL. Thethioperylenol-containing fractions 21 and 22, which were tested by HPLCanalyses, were collected and concentrated under reduced pressure. Thethioperylenol was obtained in pure form by repeated preparative HPLC onSP 250/21 NUCLEOSIL 100-7 C18 HD® columns (Macherey-Nagel, Düren) usingthe eluent 0.1% ammonium formate, pH 4.8, in water/95% acetonitrile in agradient method. The flow rate through the column was 25 mL/minute andthe thioperylenol was eluted from the separating column with anacetonitrile content of about 25%. 10 mg of crystalline thioperylenolwere obtained by slowly concentrating under reduced pressure.

EXAMPLE 5 High-Pressure Liquid Chromatography (HPLC) of theThioperylenol

[0119] Column: YMC-Pack Pro C18 ®, AS-303, 250 × 4.6 mm, S-5 μm; MobilePhase: 0 to 2 minutes: 0.02% trifluoroacetic acid (TFA), 2 to 20minutes: 0% to 100% acetonitrile in 0.1% TFA, 20 to 25 minutes: 100%acetonitrile. Flow rate: 1 mL per minute,

[0120] Detection by UV Absorption at 210 nm.

[0121] The retention time for thioperylenol was found to be 12.1minutes.

EXAMPLE 6 Properties of Thioperylenol

[0122] The physicochemical and spectroscopic properties of thioperylenolcan be summarized as follows:

[0123] Appearance:

[0124] Brownish crystals which are soluble in medium-polar and polarorganic solvents and soluble in aqueous neutral buffers. Stable inneutral and mildly acidic, non-oxidizing medium but unstable in stronglyacidic and strongly alkaline solution. Empirical formula: C₂₃H₂₀O₉S,molecular weight: 472.47 ¹H and ¹³C NMR: see table 1;

[0125] UV maxima in water/acetonitrile (1 to 1), pH 3.0: 216 nm, 259 nm,292 nm and 383 nm. TABLE 1 Chemical shifts of V-2474 in DMSO at 300K.Position ¹H ¹³C 1 — 160.14 2 7.01 118.22 3 8.05 132.57 4 — 125.12 5 —137.09 6 — 113.86 7 — 122.82 8 7.53 123.75 9 6.79 113.50 10 — 156.37 11— 122.66 12 — 128.08 13 — 204.10 14 3.62/3.06 ˜39.1 15 4.29 46.56 16 —70.80 17 3.64 41.35 18 3.93 49.15 19 3.44 55.30 20 5.11 59.67 212.92/2.76 36.23 22 3.72 72.96 23 — 174.38

EXAMPLE 7 Mass Spectrometric Characterization of Thioperylenol

[0126] Thioperylenol is assigned the mass of 472 on the basis of thefollowing findings: the ESI⁺ spectrum gave weak peaks at 490 amu(M+NH₄)⁺ and 962 amu (2M+NH₄)⁺. The ESI⁻ spectrum gave a peak, interalia, at 471 amu (M−H)⁺.

[0127] Using an FTICR mass spectrometer, a peak was observed, interalia, at 569.0525 amu in the ESI— mode and in the added presence ofphosphoric acid. The measured value agrees well with that calculated for(M+H₂PO₄)⁻=C₂₃H₂₂O₁₃PS=569.0524 amu (0.2 ppm difference).

[0128] MS/MS experiments using an FTICR mass spectrometer led to thefollowing fragmentations in the ESI⁻ mode:

[0129] 471 amu to 349 amu (—C₃H₆O₃S), 331 amu (—C₃H₈O₄S), 313 amu(—C₃H₁₀O₅S), 303 amu (—C₄H₈O₅S), 285 amu (—C₄H₁₀O₆S), 261 amu(—C₆H₁₀O₆S) and smaller fragments.

PHARMACOLOGICAL EXAMPLES

[0130] The inhibition of platelet aggregation can be measured, interalia, by determining platelet aggregation turbimetrically as describedby Born (Born, GV, Nature, 1962,194: 927-929).

[0131] Principle of the test: the method is based on the property thatthe optical density of a particle suspension depends on the number ofparticles and not on their size. After a platelet suspension has beenstimulated, the platelets begin to aggregate. This leads to theappearance of relatively large platelet aggregates and to an increase inlight transmission. This increase is registered photometrically, andrecorded in curve form, continuously. The degrees to which thethrombocytes can be aggregated, or to which this aggregation can beinhibited, can be deduced from the changes in light transmission. Themethod of staining cells with calcein was used for determiningcytotoxicity (Hollo Z et al., Biochim Biophys Acta 11;1191(2):384-8,1994). Living cells incorporate the substrate calcein acetoxymethylester (C-AM), which is hydrolyzed in the cells by nonspecific esterases.C-AM is colorless and does not fluoresce. In the living cell, it isconverted into the fluorescent hydrolysis product and the vitality ofthe cells can be measured on the basis of the fluorescence (λ_(ex):485nm/λ_(em):538 nm).

[0132] By way of example, Table 2 summarizes the inhibitory effects ofsome hydroperylene derivatives as IC₅₀ values. The IC₅₀ value indicatesthe concentration which inhibits thrombocyte aggregation by 50% underdefined conditions. TABLE 2 The concentrations of some hydroperylenederivatives which inhibit thrombocyte aggregation by 50% (IC₅₀).Compound IC₅₀ (platelet aggregation) IC₅₀ (toxicity) Thioperylenol 7.2μM 61 μM Alterperylenol 1.6 μM >100 μM Altertoxin I 29 μM >100 μMAltertoxin II 2.6 μM 10 μM Altertoxin III 6.1 μM 20 μM

[0133] As can be seen from the table, in addition to inhibitingthrombocyte aggregation, some of the hydroperylene derivatives alsoexhibit a substantial degree of cell toxicity. The cell toxicity isparticularly marked in the case of compounds which carry epoxide groups.For this reason, those compounds of the formula I which, whilepossessing an inhibitory effect on platelet aggregation, are relativelynontoxic are particularly valuable. Preference is consequently given tohydroperylenol derivatives which are epoxide-free.

EXAMPLE 8 Test for Inhibition of Thrombocyte Aggregation

[0134] The following reagents are required for implementing thethrombocyte aggregation test: Materials Supplier Catalogue No. Watertissue culture grade Sigma W-3500  NaCl Merck 1.06404 KCl Merck 1.04933CaCl₂ Merck 1.02083 Albumin, bovine (BSA) Sigma A-6003 Calcein AMMolecular Probes C-1430 Collagen reagent Nycomed 5368 Human alphaThrombin Haemochrom Diagnostica HT1002A

[0135] The assay was carried out as follows:

[0136] Tyrode Buffer: NaCl 120 mM KCl 2.6 mM NaHCO3 12 mM NaH₂PO₄ × H₂O0.39 mM Hepes 10 mM Glucose 5.5 mM BSA 0.35%

[0137] Add fresh glucose and BSA daily

[0138] Adjust pH to 7.4

[0139] Calcein AM: 1 mg of Calcein AM in 1 ml of DMSO (1 mM)

[0140] Human α-thrombin (stock solution): 1000 units in 1 ml of 0.9%NaCl

[0141] Final concentration of activator: 0.05 U of thrombin/ml or 1 pgof collagen/ml

[0142] Wortmannin, stock solution: 1 mg in 233.43 μl of DMSO (10 mM).

[0143] Aggregation in Aggregometer (PAP 4)

[0144] Cell number, 3×10⁵ thrombocytes/μl

[0145] Mixture in siliconized glass microtubes

[0146] Total volume, 400 μl/tube

[0147] Per Microtube:

[0148] 320 μl of thrombocytes

[0149] 20 μl of 10 mM CaCl₂ (f.c. 0.5 mM)

[0150] 20 μl of test substance

[0151] 40 μl of agonist

[0152] Controls: Blank: 400 μl of buffer (Tyrode, 0.35% BSA) Negativecontrol: 320 μl of thrombocytes 40 μl of CaCl₂ 5 mM (f.c. 0.5 mM) 40 μlof buffer Positive control: 320 μl of buffer 40 μl of 5 mM CaCl₂ (f.c.0.5 mM) 40 μl of activator

[0153] The blank value for the channels of the aggregometer is first ofall adjusted using buffer. The thrombocytes are then pipetted intomicrotubes and, after the thrombocytes have been added, heated at 37° C.for a few minutes in the aggregometer. After a magnetic stirrer has beenadded to each reaction tube, the substances, and CaCl₂, are added and astart is made in recording the course of the curve in the aggregometer.After 2 minutes of incubation, the activator, or buffer in the case ofthe control, is added. The course of the curve is then recorded for afurther 6 min at 37° C. and at a stirrer speed of 1050 revolutions perminute.

1. A compound of formula I

including all stereoisomeric forms of said compound of formula I,mixtures of said forms and compounds in any ratio, and/ physiologicallytolerated salts thereof, wherein: R1, R2, R3, R4, R5, R6, R7, R8, R10and R11 are independently selected from the group consisting ofhydrogen; (C₁-C₆)-alkyl, in which alkyl is a straight or branched chainand is unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —OH; ═O;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: : —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;-aryl, in which aryl is unsubstituted or substituted by one, two orthree substituents independently selected from the group consisting of:halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain; —OHand —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain andis substituted by one, two or three substituents selected from the groupconsisting of halogen; —C(O)—OH; —C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, inwhich alkyl is a straight or branched chain; —NH—(C₁-C₆)-alkyl, in whichalkyl is a straight or branched chain and is unsubstituted orsubstituted by one, two or three substituents independently selectedfrom the group consisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl,in which alkyl is a straight or branched chain; —NH—(C₂-C₆)-alkenyl, inwhich alkenyl is a straight or branched chain and is unsubstituted orsubstituted by one, two or three substituents independently selectedfrom the group consisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl,in which alkyl is a straight or branched chain; —NH—(C₂-C₆)-alkynyl, inwhich alkynyl is a straight or branched chain and is unsubstituted orsubstituted by one, two or three substituents independently selectedfrom the group consisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl,in which alkyl is a straight or branched chain; —NH₂ and halogen;(C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —OH; ═O;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain and isunsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkenyl, in which alkenyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;—O—(C₂-C₆)-alkynyl, in which alkynyl is a straight or branched chain andis unsubstituted or substituted by one, two or three substituentsindependently selected from the group consisting of: : —CN; —NH₂; ═N—OHand ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain;-aryl, in which aryl is unsubstituted or substituted by one, two orthree substituents independently selected from the group consisting of:halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain;—O—(C₁-C₆)-alkyl, in which alkyl is a straight or branched chain; —OHand —(C₁-C₄)-alkyl, in which alkyl is a straight or branched chain andis substituted one, two or three times by halogen; —C(O)—OH;—C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —NH₂ and halogen; (C₂-C₆)-alkynyl, in which alkynyl is astraight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —OH; ═O; —O—(C₁-C₆)-alkyl, in which alkyl is a straightor branched chain and is unsubstituted or substituted by one, two orthree substituents independently selected from the group consisting of:—CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)— alkyl, in which alkyl is a straight orbranched chain; —O—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; -aryl, in which aryl is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —OH and —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain and is substituted one, two or three times by halogen;—C(O)—OH; —C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is astraight or branched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is astraight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkenyl, in which alkenylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkynyl, in which alkynylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH₂ and halogen; —O—R⁹, in which R⁹ isselected from the group consisting of: (C₁-C₆)-alkyl, in which alkyl isa straight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —OH; ═O; —O—(C₁-C₆)-alkyl, in which alkyl is a straightor branched chain and is unsubstituted or substituted by one, two orthree substituents independently selected from the group consisting of:—CN; —NH₂; ═N—OH; and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straightor branched chain; —O—(C₂-C₆)-alkenyl, in which alkenyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₂-C₆)-alkynyl, in which alkynyl is a straight orbranched chain and is unsubstituted or substituted by one, two or threesubstituents independently selected from the group consisting of: —CN;—NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; -aryl, in which aryl is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: halogen; —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain; —O—(C₁-C₆)-alkyl, in which alkyl is a straight orbranched chain; —OH and —(C₁-C₄)-alkyl, in which alkyl is a straight orbranched chain and is substituted one, two or three times by halogen;—C(O)—OH; —C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl is astraight or branched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is astraight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH; and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkenyl, in which alkenylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkynyl, in which alkynylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH₂ and halogen; (C₂-C₆)-alkenyl, inwhich alkenyl is a straight or branched chain and is unsubstituted orsubstituted by one, two or three substituents independently selectedfrom the group consisting of:—OH; ═O; —O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH; and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —O—(C₂-C₆)-alkenyl, in which alkenyl isa straight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —O—(C₂-C₆)-alkynyl, in which alkynyl isa straight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; -aryl, in which aryl is unsubstitutedor substituted by one, two or three substituents independently selectedfrom the group consisting of: halogen; —(C₁-C₄)-alkyl, in which alkyl isa straight or branched chain; —O—(C₁-C₆)-alkyl, in which alkyl is astraight or branched chain; —OH and —(C₁-C₄)-alkyl, in which alkyl is astraight or branched chain and is substituted one, two or three times byhalogen; —C(O)—OH; —C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl isa straight or branched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is astraight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH; and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkenyl, in which alkenylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkynyl, in which alkynylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH₂ and halogen; (C₂-C₆)-alkynyl, inwhich alkynyl is a straight or branched chain and is unsubstituted orsubstituted by one, two or three substituents independently selectedfrom the group consisting of:—OH; ═O; —O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH; and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —O—(C₂-C₆)-alkenyl, in which alkenyl isa straight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —O—(C₂-C₆)-alkynyl, in which alkynyl isa straight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; -aryl, in which aryl is unsubstitutedor substituted by one, two or three substituents independently selectedfrom the group consisting of: halogen; —(C₁-C₄)-alkyl, in which alkyl isa straight or branched chain; —O—(C₁-C₆)-alkyl, in which alkyl is astraight or branched chain; —OH and —(C₁-C₄)-alkyl, in which alkyl is astraight or branched chain and is substituted one, two or three times byhalogen; —C(O)—OH; —C(O)—O—NH₂; —C(O)—O—(C₁-C₄)-alkyl, in which alkyl isa straight or branched chain; —NH—(C₁-C₆)-alkyl, in which alkyl is astraight or branched chain and is unsubstituted or substituted by one,two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH; and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkenyl, in which alkenylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH—(C₂-C₆)-alkynyl, in which alkynylis a straight or branched chain and is unsubstituted or substituted byone, two or three substituents independently selected from the groupconsisting of: —CN; —NH₂; ═N—OH and ═N—O—(C₁-C₆)-alkyl, in which alkylis a straight or branched chain; —NH₂ and halogen; —NH—R⁹, in which R⁹is as defined above; —NH—C(O)—H; —NH—C(O)—R⁹, in which R⁹ is as definedabove; —NH-aryl, in which aryl is unsubstituted or independentlysubstituted one, two or three times by R⁹, in which R⁹ is as definedabove: ═N—OH; ═N—O—R⁹, in which R⁹ is as defined above; —S—H; —S—R⁹, inwhich R⁹ is as defined above; —S(O)—R⁹, in which R⁹ is as defined above;—S(O)₂—R⁹, in which R⁹ is as defined above; and —SO₂, with the followingfurther alternatives to the foregoing definition: a) either R4 and R5 orR10 and R11, together with the carbon atoms to which theyare,respectively, bonded, may form a 3-, 4-, 5- or 6-memberedheteroalkyl or heteroaryl ring system which contains one or twoheteroatoms selected from the group consisting of oxygen, nitrogen andsulfur; and b) the bond between the ring carbons indicated as —C₁₄-C₁₅—in formula I may be either a single bond or a double bond; and thefurther proviso that: c) R7 is not hydrogen.
 2. A compound of theformula I as claimed in claim 1, wherein a) each of R1, R2, R3 and R6 is—OH, b) R4 and R5, together with the carbon atoms to which they arebonded, form an epoxide, c) R7 is the radical —S—CH₂—CHOH—COOH, d) R8 is═O, e) each of R10 and R11 is hydrogen atom; and f) the bond between thering carbons designated as —C₁₄-C₁₅— is a single bond, and/orphysiologically tolerated salts thereof of the compound of the formulaI.
 3. A compound as claimed in claim 2, which has the structure offormula II


4. A process for preparing a compound of formula I as claimed in claim1, which comprises a) culturing the microorganism DSM 14452, or a mutantor variant thereof, in an aqueous nutrient medium; b) isolating from theculture medium of step a) the compound thioperylenol; c) purifying thethiophenyl thus obtained; d) converting thioperylenol, whether or notobtained by the foregoing steps, by means of chemical derivatization,into a compound of the formula I; e) if necessary, i) resolving thecompound of the formula I so obtained, which, because of its chemicalstructure, appears in enantiomeric forms, into its pure enantiomerseither by forming salts with enantiomerically pure acids or bases, or bychromatography on chiral stationary phases or by derivatizing withchiral, enantiomerically pure compounds, such as amino acids, ii)separating the diastereomers which are thus obtained and iii)eliminating the chiral auxiliary groups; and f) optionally, eitherisolating the compound of the formula I which has been thus prepared infree form or, when acidic or basic groups are present, converting itinto a physiologically tolerated salts.
 5. The microorganism DSM 14452.6. A pharmaceutical composition which contains a therapeuticallyeffective amount of at least one compound as claimed in claim 1,together with a pharmaceutically suitable and physiologically toleratedcarrier substance or additive and/or other active compounds andauxiliary substances.
 7. A method of treating or preventing diseases inwhich high blood platelet aggregations occur, comprising administeringto a mammal in need thereof an effective amount of a compound of claim 1in pharmaceutically acceptable form.
 8. The method of claim 7 whereinsaid compound is as defined in claim
 2. 9. The method of claim 7,wherein said compound is selected from the group consisting of:thioperylenol, a compound of formula I, in which: R1, R2, R3 and R6 are,in each case, —OH; R4 and R5, together with the carbon atoms to whichthey are in each case bonded, form an epoxide; R7 is the radical—S—CH₂—CHOH—COOH; R8 is ═O; R10 and R11 are, in each case, hydrogen; andthe bond between —C₁₄-C₁₅-is a single bond; alterperylenol, a compoundof formula I, in which R1, R2, R5 and R6 are, in each case, —OH; R3 andR8 are, in each case, ═O; R4, R7, R10 and R11 are, in each case,hydrogen; and the bond between —C₁₄-C₁₅— is a double bond; altertoxin 1,a compound of formula I in which R1, R2, R5 and R6 are, in each case,—OH; R3 and R8 are, in each case, ═O; R4, R7, R10 and R11 are, in eachcase, hydrogen; and the bond between —C₁₄-C₁₅— is a single bond;altertoxin 11, a compound of formula I, in which R1, R2 and R6 are, ineach case, —OH; R3 and R8 are in each case ═O; R4 and R5, together withthe carbon atoms to which they are in each case bonded, form an epoxide;R7, R10 and R11 are, in each case, hydrogen; and the bond between—C₁₄-C₁₅— is a single bond; and altertoxin III, a compound of formula I,in which R1 and R3 are, in each case, ═O, R2 and R8 are, in each case,—OH; R4 and R5 and R10 and R11, together with the carbon atoms to whichthey are in each case bonded, form an epoxide; R6 and R7 are, in eachcase, hydrogen; and the bond between —C₁₄-C₁₅— is a single bond.
 10. Themethod of claim 7, wherein said disease in which high blood plateletaggregations occur is selected from the group consisting of myocardialinfarction, unstable angina pectoris, stroke, transitory ischemicattacks and peripheral arterial occlusion diseases such as intermittentclaudication.